The present invention relates to the use of active substances for preparing a medicament controlling the plasma level of the lipoproteins lipoprotein(a) (Lp(a)) and high-density lipoprotein (HDL) by decreasing the synthesis of apolipoprotein(a) (apo(a)) and by increasing the synthesis of apolipoprotein A1 (apo A1). In particular, the invention relates to the novel use of antagonists of platelet activating factor (PAF-antagonists) and of structurally related compounds, which do not necessarily possess PAF-antagonistic activity, for preparing such medicaments.
Apolipoprotein A-I (apo A-I) is the major protein constituent of plasma high density lipoprotein (HDL) (1). In mammals, the protein is mainly synthesized in the liver and the small intestine (1,2). Decreased plasma levels of HDL cholesterol are associated with an accelerated development of atherosclerotic lesions, which is,one of the main causes of coronary artery disease (3-5). The plasma level of apo A-I has been reported to be even more discriminatory in determining the risk of cardiovascular disease than the cholesterol concentration of HDL (6, 7).
Several drugs (e.g. fibrates and statins, summarized in refs. 5 and 12) are currently us use to lower plasma lipid levels, which secondarily increase plasma HDL levels. However, their HDL increasing effects are small in general and most of them, perhaps with the exception of gemfibrozil, appear to act indirectly, i.e. no direct effect on apo A-I synthesis is found (5,12). Recently, a series of urea-type compounds and thiazolo-[3,2-c]pyrimidine-5,7-diones have been claimed as HDL-elevators (see ref 95, 96 in 12).
A high plasma level of lipoprotein(a) (Lp(a)) is positively associated with the development of coronary heart disease and cerebrovascular disease in men and women, especially when plasma levels exceed 0,20-0,30 g/l and when LDL levels are concomitantly increased (13-15). In Lp(a) the apoprotein (a), which is synthesized in the liver, is covalently bound to an LDL particle. This binding is thought to take place extracellularly at the cell surface (12), in vivo turnover studies in humans indicated that Lp(a) levels are mainly influenced by Lp(a) and apo(a) production rates and not by Lp(a) clearance rates, emphasizing the importance of apo(a) synthesis for plasma Lp(a) levels (16, 17).
No satisfactory pharmacological treatment for raised Lp(a) levels exists currently. Of the established hypolipidemic drugs only nicotinic acid and perhaps some fibrates, as well as LDL apheresis treatment lower Lp(a) levels, but these therapies are inadequate in terms of efficacy, specificity and palatability (12, 14, 15).
Apo B-100 is the sole protein of LDL. Increased levels of LDL-cholesterol and apo B-100 in blood are strongly associated with the development of atherosclerosis and the incidence of coronary heart disease (8-11).
It was found that administration of certain compounds which have PAF (platelet activating factor) antagonistic activity and structurally related compounds, which may or may not have such activity, results in a reduced synthesis of apolipoprotein(a) (apo(a)) and/or, independently, in an enhanced synthesis of apolipoprotein AI (apo AI).
In a first aspect the invention pertains to the use of compounds active as PAF-antagonists and structurally related compounds, which need not be active as PAF-antagonists, in the prevention and treatment of atherogenic conditions in mammals including man, by decreasing lipoprotein (a) (Lp(a)) levels in plasma. Such compounds may comprise azepine derivatives having the following formula 1: 
benzoazepine derivatives having the following formula 1a: 
wherein A is a group xe2x80x94CHxe2x95x90C(R2)xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Sxe2x80x94C(R2)xe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90C(R2)xe2x80x94Sxe2x80x94 or an optionally substituted benzo or thieno ring having the following formula 1b: 
Q is a nitrogen atom (xe2x80x94Nxe2x95x90), or an optionally substituted carbon atom (xe2x80x94CR4xe2x95x90), R4 being as defined below;
X is a nitrogen, sulphur or oxygen atom, the neighboring bond optionally being a double bond if X is nitrogen;
Y is a nitrogen atom (xe2x95x90Nxe2x80x94) or an optionally substituted carbon atom (xe2x95x90CRxe2x80x94), having a substituent R wherein R is hydrogen, methyl, ethyl, methoxycarbonyl or ethoxycarbonyl;
Z is a nitrogen atom (xe2x80x94Nxe2x95x90) or an optionally methyl-substituted carbon atom (xe2x80x94CRxe2x80x2xe2x95x90) having a substitutent Rxe2x80x2 wherein R1 is hydrogen, methyl or hydroxymethyl;
at least one of Y and Z is a nitrogen atom;
R1 is hydrogen, halogen, C1-C6 alkyl, cycloalkylalkyl or cycloalkylalkenyl, trifluoromethyl, hydroxymethyl or aminomethyl,
R2 is hydrogen, halogen, trifluoromethyl, nitro, C1-C3 alkyl or the group xe2x80x94CH2xe2x80x94CH2R2, R2xe2x80x2 being an optionally substituted phenyl, C1-C3 alkoxycarbonyl, or an aminomethyl or carbamoyl group, the nitrogen atom of the aminomethyl or carbamoyl group optionally being substituted by one or two C1-C3 alkyl groups or optionally being part of a pyrrolidino, piperidino, or morpholino ring;
R3 is hydrogen, hydroxyl, methyl or carboxyl; and
R4 is hydrogen, halogen, hydroxyl, methyl or methoxy;
and substituted tetrahydrofuran phospholipid analogues having the following formula 2: 
xe2x80x83wherein D is xe2x80x94CR7xe2x95x90CR7xe2x80x94 or xe2x80x94Sxe2x80x94,
R5 and R6 are independently hydrogen, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, or together are xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH)4xe2x80x94 or xe2x80x94CH2OCH2xe2x80x94,
each R7 is independently hydrogen, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy,
R8 is C8-C20 alkyl, alkenyl, cycloalkyl-alkyl or arylalkyl, and
n is 0 or 1,
in particular the analogue denoted as PAF-antagonist SRI 63-441.
In a second aspect the invention pertains to such compounds in the prevention and treatment of atherogenic conditions by increasing HDL levels in plasma. It should be understand that, according to the invention, xe2x80x9cstructurally relatedxe2x80x9d refers to compounds which have structural similarities, especially skeletal identity with the PAF-antagonists, but which need not be active as a PAF-antagonist.
Suitable PAF-antagonists are described, for example, by Hwang in J. Lipid Mediators, 2 (1990) 123-158 (ref. 18). Examples include various benzo- and thieno-diazepines, bis(trimethoxyphenyl)- or bis(dimethoxyphenyl)-dioxolanes and -tetrahydrofurans, especially trans-2,5bis(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-652,731) and cis- and trans-2,4-bis(3,4,5-trimethoxyphenyl)dioxolane, and various phospholipid analogues such as O-cis-5-(octadecylcarbamoyloxymethyl)-2-tetrahydrofurylmethyl O-(2-quinolinio-ethyl) hydrogen phosphate (SRI 63-441). These and other PAF-antagonists are also described by Saunders and Handley (ref. 19) and by Weber and Heuer (ref. 20).
The only effective pharmacological treatment known thus far for reducing Lp(a) levels, consists in administering nicotinic acid or its derivatives, either in combination with neomycine (3 g/day and 2 g/day respectively, see ref. 23) or alone (4 g/day, see ref. 24). Reductions of plasma levels of lp(a) were in the order of 45% and 38%, respectively.
The benzo- and thieno(di)azepines constitute an advantageous group of compounds for inhibiting apo(a) synthesis according to the invention. The benzo(di)azepines are also useful according to the invention for promoting apo A-I synthesis. Most of these compounds arc known per se. Examples of specific (di)azepines and their synthesis are described in U.S. Pat. No. 5,302,590 and in WO 96/20941.
The known effects of the benzodiazepines virtually all result from the actions of the drugs on the central nervous system. The most prominent of these effects are sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity. Only two effects of the drugs appear to result from actions on peripheral tissues: coronary vasodilatation, seen after intravenous administration of therapeutic doses of certain benzodiazepines, and neuromuscular blockade, seen only with very high doses (cf. ref. 21).
It was reported in 1984 that psychotropic triazolobenzodiazepines can inhibit the aggregation of platelets induced by platelet activating factor (22). Platelet-activating factor (PAF) is a potent inflammatory mediator with a wide variety of biological activities, such as induction of platelet and neutrophil aggregation, bronchoconstriction, hypotension and an increase in vascular permeability (19). Thus, PAF can induce a profile of biological effects which can mimic many of the major features of asthma. PAF-antagonists can be used in the management or prophylactic control of asthma or other inflammatory and allergic conditions (19,20). Many research groups were successful in separating CNS activity from PAF antagonism (20).
The benzo- and thieno- (di) azepines to be used according to the invention are defined in formulae 1, 1a and 1b above. It may be noted that the substituent represented by R2 in the cyclopentane-2-yl-1-thyl group represented by symbol A may be substituted phenyl. Examples of substituents in this respect include alkyl, alkoxy, halo, hydroxyl, carbamoyl, carboxyl and alkoxycarbonyl and combinations thereof, such as a combination of N-{3-[2-(4-cycloalkyl-2-thiazolyl) ethenyl]phenyl} carbamoyl and carboxyl, ethoxycarbonyl or carbamoyl as described in U.S. Pat. No. 5,302,590.
The diphenyl-tetrahydrofuran and diphenyl-dioxolane derivatives, as well as the tetrahydrofuran phospholipids are another group of suitable compounds according to the invention, and are defined in formula 2 hereinabove.
The specificity of the reported effects is underlined by the absence of any effect on apo B-100 and albumin synthesis.
The pharmaceutical compositions to be prepared according to the invention may be formulated in the usual way, e.g. by associating the compounds with a pharmaceutically suitable solid or liquid carrier and optional adjuvants or other active components, stabilisers, colorants, flavourings etc. The composition may be suitable for oral administration (capsule, pill, tablet, gel, powder, sachet, syrup, solution, dispersion etc.) or may be an injectable solution or another administration form (e.g. via suppositories or via plasters). The effective dose is between 0.01 and 30 mg per kg body weight per day, preferably between 0.1 and 10 mg/kg.day. A dose can be administered in a single dosage or in several daily dosages.